Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death

Huang, David C.S.; Cory, Suzanne; Strasser, Andreas

doi:10.1038/sj.onc.1200848

Cited by 239 publications

(208 citation statements)

References 49 publications

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“…1994: Yang and. A recent report demonstrated that high levels of Bcl-2 or Bcl-X, proteins are equally effective in terms of inhibiting apoptosis and suggest that the differences in their ability to block apoptosis may be due to different levels of protein expression (Huang et al 1997 Another finding of our experiments was that Bcl-X,L was predominantly expressed at steady-state levels in all of these cell lines other than Colo320 (Fiaure 2). and a slight increase in Bcl-X, expression was observed in DLD1 after exposure to 5-FU ( Figure 4D Figure 3.…”

supporting

confidence: 62%

5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins

Nita

Nagawa²,

Tominaga³

et al. 1998

Br J Cancer

145

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Summary Recently. apoptosis has been implicated as one of the end points of cells exposed to chemotherapeutic agents. The p53 and Bcl-2 family of proteins are involved in chemotherapy-induced apoptosis. but in a cell type-dependent manner. We sought to determine the roles played by the p53 and Bcl-2 family of proteins in 5-fluorouracil (5-FU)-induced apoptosis of human colon cancer cell lines. We first studied the p53 genetic and functional status, and then 5-FU, at inhibitory concentration of 50% (ICj)

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supporting

confidence: 62%

5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins

Nita

Nagawa²,

Tominaga³

et al. 1998

Br J Cancer

145

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“…To identify the apoptotic pathway that is stimulated by INNO-406, we examined the effect of INNO-406 on genetically engineered K562 subclones that overexpressed human Bcl-2 (K562/Bcl-2) or a dominant-interfering mutant of Fasassociated death domain (FADD)/MORT1 (K562/FADD-DN), which inhibits death receptor-induced apoptosis; both molecules were labeled with an N-terminal Flag tag (Figure 1c). [21][22][23] We found that Bcl-2 overexpression blocked INNO-406-induced K562 cell death, whereas FADD-DN had no effect. Moreover, BV173R, a subclone of BV173, which expresses higher levels of Bcl-2 than parental BV173 cells, was less sensitive to INNO-406-induced cell death than BV173 (Figure 1c, d).…”

mentioning

confidence: 68%

“…K562/shBim and BV173R BV173R/shBim cell lines were generated by using the anti-Bim shRNA construct cloned into the pSUPER vector. [21][22][23]39 MYL and its imatinib-resistant subclone MYL-R were kind gifts from Dr. Hideo Tanaka (Hiroshima University, Japan). 28 We generated Ba/F3-derived murine hematopoietic cell lines transformed with wt p210-Bcr-Abl (Ba/F3/wt . )…”

Section: Methodsmentioning

confidence: 99%

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

et al. 2007

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Bcr-Abl is the cause of Philadelphia-positive (Ph þ ) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph þ leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-X L , greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph þ leukemic cells.

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“…Apoptosis inducing protocols that overcome Bcl-2 include primary activation of caspases via death domain-containing receptors of the CD95/TNF-R receptor family (Huang et al, 1997;Susin et al, 1997a) or chemotherapeutic agents acting on microtubules such as taxol which may provoke Bcl-2 inactivation via hyperphosphorylation (Haldar et al, 1995(Haldar et al, , 1996. The resistance of diamide to Bcl-2 mediated cytoprotection suggests an additional strategy.…”

Section: Discussionmentioning

confidence: 99%

The thiol crosslinking agent diamide overcomes the apoptosis-inhibitory effect of Bcl-2 by enforcing mitochondrial permeability transition

et al. 1998

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In several di erent cell lines, Bcl-2 prevents the induction of apoptosis (DNA fragmentation, PARP cleavage, phosphatidylserine exposure) by the pro-oxidant terbutylhydroperoxide (t-BHP) but has no cytoprotective e ect when apoptosis is induced by the thiol crosslinking agent diazenedicarboxylic acid bis 5N,N-dimethylamide (diamide). Both t-BHP and diamide cause a disruption of the mitochondrial transmembrane potential DC m that is not inhibited by the broad spectrum caspase inhibitor Z-VAD.fmk, although Z-VAD.fmk does prevent nuclear DNA fragmentation and poly(ADP-ribose) polymerase cleavage in these models. Bcl-2 stabilizes the DC m of t-BHP-treated cells but has no inhibitory e ect on the DC m collapse induced by diamide. As compared to normal controls, isolated mitochondria from Bcl-2 overexpressing cells are relatively resistant to the induction of DC m disruption by t-BHP in vitro. Such Bcl-2 overexpressing mitochondria also fail to release apoptosis-inducing factor (AIF) and cytochrome c from the intermembrane space, whereas control mitochondria not overexpressing Bcl-2 do liberate AIF and cytochrome c in response to t-BHP. In contrast, Bcl-2 does not confer protection against diamidetriggered DC m collapse and the release of AIF and cytochrome c. This indicates that Bcl-2 suppresses the permeability transition (PT) and the associated release of intermembrane proteins induced by t-BHP but not by diamide. To further investigate the mode of action of Bcl-2, semi-puri®ed PT pore complexes were reconstituted in liposomes in a cell-free, organelle-free system. Recombinant Bcl-2 or Bcl-X L proteins augment the resistance of reconstituted PT pore complexes to pore opening induced by t-BHP. In contrast, mutated Bcl-2 proteins which have lost their cytoprotective potential also lose their PTmodulatory capacity. Again, Bcl-2 fails to confer protection against diamide in this experimental system. The reconstituted PT pore complex itself cannot release cytochrome c encapsulated into liposomes. Altogether these data suggest that pro-oxidants, thiol-reactive agents, and Bcl-2 can regulate the PT pore complex in a direct fashion, independently from their e ects on cytochrome c. Furthermore, our results suggest a strategy for inducing apoptosis in cells overexpressing apoptosis-inhibitory Bcl-2 analogs.

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Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death

Cited by 239 publications

References 49 publications

5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins

5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

The thiol crosslinking agent diamide overcomes the apoptosis-inhibitory effect of Bcl-2 by enforcing mitochondrial permeability transition

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